Acute uncomplicated urinary tract infections (DTI) occur in an estimated 7-11 million women each year at a cumulative cost estimated to exceed $1 billion annually. Approximately 20-30% of women suffer from frequent recurrent infections. UTI in young women result in substantial morbidity, time lost from work, and medical costs. An improved understanding of the pathogenic mechanisms underlying UTI could result in new diagnostics and novel approaches to prevention and treatment resulting in tailored therapies, decreased antimicrobial use, and decreased morbidity. The goal of this project is to prospectively follow a well defined group of patients from acute to recurrent UTI and obtain clinical samples to better understand UTI pathogenesis. The clinical samples will be analyzed throughout this and the accompanying 2 projects to understand the ecological niches in which uropathogens reside and persist, the host responses to the primary acute infection and persistence, and uropathogen virulence repertoires that dictate the interplay between pathogen and host resulting in different clinical syndromes such as acute cystitis and asymptomatic bacteruria. In this project, we will prospectively follow a large cohort of women from single isolated acute to recurrent UTI to determine 1) the innate immune response to infection in patients who have a single isolated UTI vs. those with recurrent infection, differentiating same strain and different strain recurrence and correlating elements of the innate response with urovirulence characteristics of the infecting strain, 2) the adaptive response to infection of patients who have a single acute event vs. those with recurrent infection and 3) the association of intracellular bacterial communities (IBC) and IBC derived factors with recurrent UTI. Through translation from clinical to basic molecular studies, this project will identify unique host responses to same strain and different strain recurrent UTI. Uropathogenic strains isolated from well-characterized episodes of UTI and asymptomatic bacteriuria will be used in Project 1 for comparative genomics to identify and test the virulence repertoire necessary for different subtypes of UTI. The molecular pathogenesis of representative strains and the contribution of specific virulence factors to disease will also be examined in Project 1. Uncultured genitourinary tract samples will be evaluated for the evolution of the microbial ecology from acute to recurrent UTI in Project 3. Together these studies will bring together key elements of UTI epidemiology and molecular pathogenesis to develop optimal management and preventative strategies.